Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors
Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors
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DOI：
10.1158/1078-0432.ccr-14-2607
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发表时间：
2015-10-01
影响因子：
11.5
通讯作者：
Tolcher, Anthony W.
中科院分区：
文献类型：
--
作者：
Patnaik, Amita;Kang, S. Peter;Tolcher, Anthony W.
目的：本I期研究评估了pembrolizumab在晚期实体瘤患者中的安全性、最大耐受剂量、抗肿瘤活性、药代动力学和药效学。实验设计：在一项3 + 3剂量递增研究中，10名患者每2周静脉注射1、3或10 mg/kg的派姆单抗，直到出现进展或无法忍受的毒性。另外7名患者每2周接受10mg /kg的治疗。13名患者参加了为期3周的患者内剂量递增（剂量范围为0.005-10 mg/kg），随后每3周增加2或10 mg/kg。根据实体肿瘤反应评价标准（RECIST） 1.1版评估肿瘤反应。结果：未见剂量限制性毒性反应。最大给药剂量为每2周10mg /kg。一名黑色素瘤患者和一名默克尔细胞癌患者的完全缓解时间分别为57周和56周以上。三名黑色素瘤患者出现了部分反应。15例不同恶性肿瘤患者病情稳定。1例患者在pembrolizumab停药92天后死于隐球菌感染，此前长期使用皮质类固醇治疗被认为与药物相关的2级胃炎。派姆单抗表现出人源化单克隆抗体典型的药代动力学特征。在每3周大于或等于1 mg/kg的谷剂量水平下，达到了最大血清靶作用。以肿瘤内暴露预测为重点的基于机制的转化模型表明，每3周剂量>= 2mg /kg时，将观察到强劲的临床活性。结论：Pembrolizumab耐受性良好，在多发性实体瘤中具有持久的抗肿瘤活性。具有充分抗肿瘤活性的最低剂量为每3周2 mg/kg。(c) 2015年aacr。
Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors.Experimental Design: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005-10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.Results: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses >= 2 mg/kg every 3 weeks.Conclusions: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks. (C) 2015 AACR.